Substituted triazole compounds as serine protease inhibitors

Abstract

There are provided inter alia multisubstituted aromatic compounds useful for the inhibition of thrombin and/or kallikrein, which compounds include substituted triazolyl. There are additionally provided pharmaceutical compositions. There are additionally provided methods of treating and preventing certain diseases or disorders, which diseases or disorders are amenable to treatment or prevention by the inhibition of thrombin and/or kallikrein.

What is claimed is: 
     
         1 . A compound with the following structure: 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salt, ester, solvate, or prodrug thereof, wherein: 
         L 1  and L 2  are independently a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, —C(O)—, —S—, —SO—, —SO 2 —, —O—, —NHSO 2 —, —NHC(O)—, or —NR 4 —; 
         R 1  and R 2  are independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted fused ring aryl, or substituted or unsubstituted heteroaryl; 
         R 4  is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted fused ring aryl, or substituted or unsubstituted heteroaryl; 
         V is hydrogen or substituted or unsubstituted alkyl; 
         W is absent, hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —C(O)R 6 , —C(O)OR 6 , —SR 6 , —SOR 6 , —SO 2 R 6 , —SO 2 NR 6 R 7 , —OR 6 , —NHSO 2 R 6 , or —NR 6 R 7 , where R 6  and R 7  are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycloalkenyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein R 6  and R 7  can be combined if both are present to form a substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; 
         X is a bond, substituted or unsubstituted alkylene, —O—, or —NR 8 —; 
         Y is a bond, substituted or unsubstituted alkylene, —O—, or —N—, provided that when Y is —O—, W is absent; and 
         Z is a bond, —C(O)—, substituted or unsubstituted alkylene, —O—, or —NR 9 —; 
         wherein R 8  and R 9  are independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —C(O)R 6 , —C(O)OR 6 , —C(O)NR 6 R 7 , —SR 6 , —SOR 6 , —SO 2 R 6 , —SO 2 NR 6 R 7 , —OR 6 , —NHSO 2 R 6 , or —NR 6 R 7 , wherein R 6  and R 7  are as defined above; and 
         provided that either at least one of X is —O— or —NR 8 —, Y is —O— or —N—, or Z is —O— or —NR 9 —. 
       
     
     
         2 . The compound of  claim 1 , wherein X is a bond or substituted or unsubstituted alkylene. 
     
     
         3 . The compound of  claim 2 , wherein Z is a bond or substituted or unsubstituted alkylene. 
     
     
         4 . The compound of  claim 3 , wherein Y is —N—, and W is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, —C(O)R 6 , —C(O)OR 6 , —C(O)NR 6 R 7 ′—SO 2 R 6 , or SO 2 NR 6 R 7 , wherein R 6  and R 7  are independently substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl, or R 6  and R 7  can be combined if both are present to form a substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. 
     
     
         5 . The compound of  claim 4 , wherein X is selected from the group consisting of substituted or unsubstituted methylene, substituted or unsubstituted ethylene, substituted or unsubstituted propylene, substituted or unsubstituted butylene, and substituted or unsubstituted pentylene, and Z is a bond. 
     
     
         6 . The compound of  claim 4 , wherein X is a bond, and Z is selected from the group consisting of substituted or unsubstituted methylene, substituted or unsubstituted ethylene, substituted or unsubstituted propylene, substituted or unsubstituted butylene, and substituted or unsubstituted pentylene. 
     
     
         7 . The compound of  claim 4 , wherein X is selected from the group consisting of substituted or unsubstituted methylene, substituted or unsubstituted ethylene, substituted or unsubstituted propylene, substituted or unsubstituted butylene, and substituted or unsubstituted pentylene, and wherein Z is selected from the group consisting of substituted or unsubstituted methylene, substituted or unsubstituted ethylene, substituted or unsubstituted propylene, substituted or unsubstituted butylene, and substituted or unsubstituted pentylene. 
     
     
         8 . The compound of  claim 7 , wherein X and Z are both branched alkylene and X and Z are covalently attached. 
     
     
         9 . The compound of any of  claims 6 - 8 , wherein Z is selected from the group consisting of substituted methylene, substituted ethylene, substituted propylene, substituted butylene, and substituted pentylene, having one or more substituent groups selected from the group consisting of —OH, —NH 2 , —SH, —CN, —CF 3 , —NO 2 , oxo, halogen, —COOH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 
     
     
         10 . The compound of  claim 4 , wherein X is selected from the group consisting of substituted or unsubstituted methylene, substituted or unsubstituted ethylene, substituted or unsubstituted propylene, substituted or unsubstituted butylene, and substituted or unsubstituted pentylene, and wherein Z is —C(O)—. 
     
     
         11 . The compound of any of  claims 4 - 10 , wherein W is hydrogen. 
     
     
         12 . The compound of any of  claims 4 - 10 , wherein W is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, —C(O)R 6 , —C(O)OR 6 , —C(O)NR 6 R 7 ′—SR 6 , —SOR 6 , —SO 2 R 6 , and —SO 2 NR 6 . 
     
     
         13 . The compound of  claim 12 , wherein W is substituted alkyl, substituted heteroalkyl, substituted alkenyl, substituted heteroalkenyl, substituted cycloalkyl, or substituted heterocycloalkyl, having one or more substituent groups selected from the group consisting of —OH, —NH 2 , —SH, —CN, —CF 3 , —NO 2 , oxo, halogen, —COOH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 
     
     
         14 . The compound of  claim 12 , wherein W is —COR 6 , —C(O)OR 6 , —C(O)NR 6 R 7 , —SO 2 R 6  or —SO 2 NR 6 R 7 , and wherein R 6  and R 7  are selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, or R 6  and R 7  combine to form a substituted or unsubstituted alkylene. 
     
     
         15 . The compound of  claim 1 , wherein W is absent, X is —NR B —, Y is a bond or substituted or unsubstituted alkylene, and Z is —NR 9 —. 
     
     
         16 . The compound of  claim 15 , wherein Y is selected from the group consisting of substituted or unsubstituted methylene, substituted or unsubstituted ethylene, substituted or unsubstituted propylene, substituted or unsubstituted butylene, and substituted or unsubstituted pentylene. 
     
     
         17 . The compound of  claim 16 , wherein R 8  is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heteroalkenyl, —COR 6 , —C(O)OR 6 , —C(O)NR 6 R 7 , —SR 6 , —SOR 6 , —SO 2 R 6 , and —SO 2 NR 6 R 7 , and wherein R 9  is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heteroalkenyl, —COR 6 , —C(O)OR 6 , —C(O)NR 6 R 7 , —SR 6 , —SOR 6 , —SO 2 R 6 , and —SO 2 NR 6 R 7 . 
     
     
         18 . The compound of  claim 3 , wherein Y is —O—, and W is absent. 
     
     
         19 . The compound of  claim 18 , wherein X is selected from the group consisting of substituted or unsubstituted methylene, substituted or unsubstituted ethylene, substituted or unsubstituted propylene, substituted or unsubstituted butylene, and substituted or unsubstituted pentylene, and Z is a bond. 
     
     
         20 . The compound of  claim 18 , wherein X is a bond, and Z is selected from the group consisting of substituted or unsubstituted methylene, substituted or unsubstituted ethylene, substituted or unsubstituted propylene, substituted or unsubstituted butylene, and substituted or unsubstituted pentylene. 
     
     
         21 . The compound of  claim 18 , wherein X is selected from the group consisting of substituted or unsubstituted methylene, substituted or unsubstituted ethylene, substituted or unsubstituted propylene, substituted or unsubstituted butylene, and substituted or unsubstituted pentylene, and wherein Z is selected from the group consisting of substituted or unsubstituted methylene, substituted or unsubstituted ethylene, substituted or unsubstituted propylene, substituted or unsubstituted butylene, and substituted or unsubstituted pentylene. 
     
     
         22 . The compound of any of  claims 1 - 21 , wherein V is hydrogen or substituted or unsubstituted methyl. 
     
     
         23 . The compound according to any of  claims 1 - 22 , wherein L 1  is —S—, —O—, —NR 4 —, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; R 1  is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted fused ring aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl; and R 4  is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heterocycloalkyl. 
     
     
         24 . The compound according to  claim 23 , wherein L 1  is —NR 4 — or substituted or unsubstituted heteroalkyl, and R 1  is substituted or unsubstituted alkyl or substituted or unsubstituted heteroaryl. 
     
     
         25 . The compound according to  claim 24 , wherein L 1  is —NR 4 —, and R 1  is substituted alkyl having one or more substituent groups selected from the group consisting of substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl. 
     
     
         26 . The compound according to  claim 25 , wherein R 1  is substituted alkyl substituted by chloro-substituted thiophenyl. 
     
     
         27 . The compound according to  claim 24 , wherein L 1  is substituted or unsubstituted heteroalkyl, and R 1  is substituted or unsubstituted heteroaryl. 
     
     
         28 . The compound according to any of  claims 1 - 27 , wherein L 2  is bond, substituted or unsubstituted alkylene, —C(O)—, or —SO 2 —, and R 2  is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted fused ring aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl. 
     
     
         29 . The compound according to  claim 28 , wherein L 2  is bond, and R 2  is hydrogen. 
     
     
         30 . The compound according to  claim 28 , wherein L 2  is —C(O)—, and R 2  is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted fused ring aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl. 
     
     
         31 . The compound according to any of  claims 1  to  31  as set forth in Table A, Table B, or Table C. 
     
     
         32 . A pharmaceutical composition comprising a compound according to any of  claims 1  to  31 , or a compound as set forth in Table A, Table B, or Table C, and a pharmaceutically acceptable excipient. 
     
     
         33 . A method for treating and/or preventing a disease or disorder in a subject, comprising administering a compound according to any of  claims 1  to  31  or a pharmaceutical composition according to  claim 32 , to a subject in need thereof in an amount effective to treat or prevent said disease or disorder. 
     
     
         34 . The method according to  claim 33 , wherein said disease or disorder is a thrombotic disease or disorder and/or involves a blood clot thrombus or the potential formation of a blood clot thrombus. 
     
     
         35 . The method according to  claim 34 , wherein said thrombotic disease or disorder comprises acute coronary syndrome, thromboembolism, and/or thrombosis. 
     
     
         36 . The method according to  claim 35 , wherein the thromboembolism comprises venous thromboembolism, arterial thromboembolism, and/or cardiogenic thromboembolism. 
     
     
         37 . The method according to  claim 36 , wherein the venous thromboembolism comprises deep vein thrombosis and/or pulmonary embolism. 
     
     
         38 . The method according to  claim 37 , wherein the deep vein thrombosis and/or pulmonary embolism occurs following a medical procedure. 
     
     
         39 . The method according to  claim 34 , wherein said thrombotic disease or disorder involves dysfunctional coagulation or disseminated intravascular coagulation. 
     
     
         40 . The method according to  claim 39 , wherein the subject is undergoing percutaneous coronary intervention (PCI). 
     
     
         41 . The method according to  claim 34 , wherein said thrombotic disease or disorder involves a blood clot thrombus or the potential formation of a blood clot thrombus and further involves stroke and/or one or more transient ischemic attacks (TIA). 
     
     
         42 . The method according to  claim 41 , wherein said thrombotic disease or disorder involving a blood clot thrombus or the potential formation of a blood clot thrombus further involves stroke and wherein the subject has non-valvular atrial fibrillation. 
     
     
         43 . The method according to  claim 34 , wherein said thrombotic disease or disorder involves a blood clot thrombus or the potential formation of a blood clot thrombus and further involves pulmonary hypertension. 
     
     
         44 . The method according to  claim 43 , wherein the pulmonary hypertension is caused by one or more left heart disorder and/or chronic thromboembolic disease. 
     
     
         45 . The method according to  claim 43 , wherein the pulmonary hypertension is associated with one or more lung disease, including pulmonary fibrosis (idiopathic or otherwise), and/or hypoxia. 
     
     
         46 . The method according to  claim 33 , wherein said disease or disorder comprises fibrosis, Alzheimer's Disease, multiple sclerosis, pain, cancer, inflammation, and/or Type I diabetes mellitus. 
     
     
         47 . The method according to  claim 33 , wherein the disease or disorder involves recurrent cardiac events after myocardial infarction. 
     
     
         48 . The method according to  claim 36 , wherein the venous thromboembolism is associated with formation of a thrombus within a vein associated with one or more acquired or inherited risk factors and/or embolism of peripheral veins caused by a detached thrombus. 
     
     
         49 . The method according to  claim 48 , wherein the one or more risk factors comprise a previous venous thromboembolism. 
     
     
         50 . The method according to  claim 36 , wherein the cardiogenic thromboembolism is due to formation of a thrombus in the heart associated with cardiac arrhythmia, heart valve defect, prosthetic heart valves or heart disease, and/or embolism of peripheral arteries caused by a detached thrombus. 
     
     
         51 . The method according to  claim 50 , wherein the detached thrombus is in the brain (ischemic stroke). 
     
     
         52 . The method according to  claim 51 , wherein the detached thrombus causes a transient ischemic attack (TIA). 
     
     
         53 . The method according to  claim 50 , wherein the cardiogenic thromboembolism is due to non-valvular atrial fibrillation. 
     
     
         54 . The method according to  claim 35 , wherein the thrombosis is arterial thrombosis. 
     
     
         55 . The method according to  claim 54 , wherein the arterial thrombosis is due to one or more underlying atherosclerotic processes in the arteries. 
     
     
         56 . The method according to  claim 55 , wherein the one or more underlying atherosclerotic processes in the arteries obstruct or occlude an artery, cause myocardial ischemia (angina pectoris, acute coronary syndrome), cause myocardial infarction, obstruct or occlude a peripheral artery (ischemic peripheral artery disease), and/or obstruct or occlude the artery after a procedure on a blood vessel (reocclusion or restenosis after transluminal coronary angioplasty, reocclusion or restenosis after percutaneous transluminal angioplasty of peripheral arteries). 
     
     
         57 . The method according to  claim 33 , wherein the treatment or prevention comprises an adjunct therapy. 
     
     
         58 . The method according to  claim 57 , wherein the subject has myocardial infarction, and the adjunct therapy is in conjunction with thrombolytic therapy. 
     
     
         59 . The method according to  claim 57 , wherein the subject has unstable angina pectoris, thrombosis, and/or heparin-induced thrombocytopenia, and the adjunct therapy is in combination with antiplatelet therapy. 
     
     
         60 . The method according to  claim 57 , wherein the subject has non-valvular atrial fibrillation, and the adjunct therapy is in conjunction with one or more other therapies. 
     
     
         61 . The method according to  claim 33 , wherein said disease or disorder is a kallikrein-related disorder. 
     
     
         62 . The method according to  claim 61 , wherein said kallikrein-related disorder is a thrombotic disease, a fibrinolytic disease, a fibrotic disorder, a type of cancer, an inflammatory condition, or a dermatological condition. 
     
     
         63 . The method according to  claim 61 , wherein said kallikrein-related disorder is an ophthalmic disease. 
     
     
         64 . The method according to  claim 63 , wherein said compound or pharmaceutical composition is administered in the form of an ophthalmic composition applied topically to the eye. 
     
     
         65 . The method according to  claim 64 , wherein the ophthalmic composition is in the form of eye drops. 
     
     
         66 . The method according to  claim 63 , wherein said compound or pharmaceutical composition is administered in the form of an ophthalmic composition via intravitreal injection. 
     
     
         67 . The method according to  claim 63 , wherein said ophthalmic disease is diabetic macular edema, hereditary angioedema, age-related macular degeneration, or diabetic retinopathy. 
     
     
         68 . The method according to  claim 62 , wherein said type of cancer is selected from the group consisting of cervical-, testicular-, or non-small-cell lung adenocarcinoma, limited small cell lung cancer, glioma, malignant breast cancer, micrometastasis (e.g. micrometastasis of blood or liver), lung metastasis, and prostatic cancer. 
     
     
         69 . The method according to  claim 62 , wherein said inflammatory condition is sepsis, inflammatory bowel disease, inflammatory arthritis, systemic inflammatory response syndrome, or rheumatoid arthritis. 
     
     
         70 . The method according to  claim 62 , wherein said dermatological condition is atopic dermatitis, psoriasis, or Netherton Syndrome. 
     
     
         71 . The method according to any of  claims 33 - 70 , wherein said compound acts by inhibiting thrombin and/or kallikrein. 
     
     
         72 . The method according to  claim 71 , wherein said compound acts by inhibiting tissue kallikrein and/or plasma kallikrein. 
     
     
         73 . The method according to  claim 33 , wherein the amount of compound administered is a therapeutically effective dose sufficient to achieve an initial concentration of the compound or its active metabolite(s) in plasma within a range of 1-10 nM, 10-100 nM, 0.1-1 μM, 1-10 μM, 10-100 μM, 100-200 μM, 200-500 μM, or 500-1000 μM, or greater. 
     
     
         74 . The method according to  claim 73 , wherein greater than 50% of the initial compound concentration persists in the plasma for 1 hour, 3 hours, or longer, after intravenous injection. 
     
     
         75 . A compound according to any of  claims 1  to  31  or a pharmaceutical composition according to  claim 32  for use in a method according to any of  claims 33 - 74 . 
     
     
         76 . The compound according to any of  claims 1 - 31 , wherein the compound has inhibitory activity against thrombin and/or plasma kallikrein within a range of 1-10 nM, 10-100 nM, 0.1-1 μM, 1-10 μM, 10-100 μM, 100-200 μM, 200-500 μM, or 500-1000 μM, or greater.